Objectives:: To determine the effectiveness of a structured multidisciplinary non-surgical obesity therapy program on the basis of a temporary low-calorie-diet for 12 weeks, and additional intervention modules to enhance nutritional education, to increase physical activity and to modify eating behavior. Design:: Prospective multicenter observational study in obese individuals undergoing a medically supervised outpatient-based 52-week treatment in 37 centers in Germany. Subjects:: A total of 8296 participants with a body mass index (BMI) of >30 kg m−2 included within 8.5 years. Measurements:: Main outcome measures were body weight loss, waist circumference (WC), blood pressure, quality of life and adverse events. Results:: In females, initial body weight was reduced after the 1-year-intervention by 19.6 kg (95% confidence intervals 19.2–19.9 kg) and in males by 26.0 kg (25.2–26.8) according to per protocol analysis of 4850 individuals. Intention-to-treat (ITT) analysis revealed a weight reduction of 15.2 kg (14.9–15.6) in females and 19.4 kg (18.7–20.1) in males. Overall, the intervention resulted in mean reduction in WC of 11 cm; it reduced the prevalence of the metabolic syndrome by 50% and the frequency of hypertension from 47 to 29% of all participants (ITT, all P<0.001). The beneficial effects could be documented for up to 3 years and comprised significant improvement of health-related quality of life. The incidence of adverse effects was low; the only event repeatedly observed and possibly related to either the intervention or the underlying disease was biliary disorders. Conclusion:: The present non-surgical intervention program is a highly effective treatment of obesity grades I–III and obesity-related diseases, and therefore, could be a valuable basis for future weight maintenance strategies required for sustained success.